The present invention relates to microwave-assisted chemical processes and in particular relates to microwave-assisted chemical synthesis, carried out in automated, controlled-flow fashion, using heterogeneous and high-viscosity compositions and while providing for high pressure reactions.
The use of microwaves to provide energy to initiate, drive or control chemical reactions is well-established. Although conceptually microwaves can be used to affect a wide variety of chemical reactions, the commercial use of microwave assisted chemistry initially grew most rapidly in techniques such as loss-on-drying (gravimetric) moisture analysis and digestion reactions that provided the foundation for content analysis. Indeed, such reactions still represent a major part of the instrument market for microwave assisted chemistry. In particular, gravimetric analysis and digestion can often be carried out in rather robust fashion, for which the longer wavelengths and broad control parameters of microwaves are well-suited.
More recently, interest has greatly increased in using microwaves to drive more sensitive reactions, particularly organic synthesis, and to do so on the smaller scale-and thus more highly controlled basis-that is preferred (or necessary) in many research oriented applications. Both the speed and nature of microwaves offer certain advantages. Because microwaves react immediately with polar and semi-polar materials, they help avoid the lag time inherent in other forms of energy transfer such as conduction or convection heating. Thus, they offer a time advantage for many research schemes including those broadly referred to as “combinational chemistry.” Just as importantly, however, electromagnetic radiation in the microwave frequencies can affect the individual molecules (and thus compositions) somewhat differently—and thus potentially more favorably—than convection or conduction heating. Some of these advantages are explained in more detain in Hayes, Microwave Synthesis—Chemistry at the Speed of Light, 2002 CEM Publishing (ISBN 0-9722229-0-1).
As an additional factor, single mode cavity microwave instruments have become commercially available that are well-suited for controlled application of microwave radiation to small samples. These include the VOYAGER®, DISCOVER®, and EXPLORER® instruments available from CEM Corporation, Matthews, N.C., for which more formal descriptions are set forth (but not limited to) U.S. Published Patent Applications Nos. 2004/0179977, 2003/0199099, 2003/0089706, 2002/0117498, and U.S. Pat. Nos. 6,607,920, 6,521,876, 6,744,024 and 6,867,400. The contents of all of these are incorporated entirely herein by reference.
Several of these devices are batch-type devices; i.e. microwaves are applied to a fixed sample in a closed reaction vessel (or a set of fixed samples in several respective separate vessels). When an additional reaction is to be carried out, a new set of starting materials are placed in a new reaction cell which is placed in turn in the microwave cavity. Although the use of individual vessels can be automated, for the most part the reactions must be carried out in batch fashion.
For some commercial applications, however, a constant or continuous reaction scheme—i.e. exposing a continuous stream of reactants to the microwaves and producing a continuous stream of product, without intermittent manipulation of a series of vessels—is an attractive or necessary option. The present generation of instruments suitable for this type of reaction in exemplified by CEM's VOYAGER® instrument (e.g. U.S. Pat. No. 6,867,400). This type of instrument is broadly exemplified by an appropriate source of liquid starting materials, suitable fluid pumps (with those for high pressure liquid chromatography, “HPLC” being exemplary), and a flow path that carries the reactants through a microwave field for a time sufficient for a desired reaction to take place. The time spent in the microwave field is, however, dictated by the diameter and length of the flow path taken together with the flow rate of the reactants. Because practical considerations tend to limit the length of the flow path that can be conveniently placed in a commercial instrument, the time spent in the microwave field is also limited.
Although the latest generation of both the batch and continuous systems offer significant advantages for chemical synthesis, each includes characteristics that preclude it from handling certain types of reactions. The batch systems can handle high pressure and heterogeneous starting materials, but cannot offer continuous operation from a reactant source. The flow-through systems can use reactants and generate products on a continuous basis, but generally cannot handle (because of pumping or flow considerations) heterogeneous starting materials or high viscosity fluids, nor do so at high pressures. For example, conventional HPLC pumps cannot handle higher viscosity liquids or any solids whatsoever. Even if pumps that can handle solids are incorporated, however, the available flow rates raise specific problems in microwave assisted chemistry. Higher flow rates help move solids through the instrument but reduce the available time spent in the microwave field. Lower flow rates will (mathematically at least) increase residence time in the microwave field, but tend to encourage heterogeneous mixtures (typically liquid reactants and solvents in combination with solid-phase catalysts or solid-supported reagents) to separate into their respective phases before reacting properly or, in severe cases, blocking the flow path and rendering the instrument temporarily or permanently unusable.
Flow-through devices also lack a stirring capability, which can be particularly important for heterogeneous mixtures. Furthermore, precise temperature control (as opposed to consistent application of microwave radiation) is difficult or impossible in flow-through systems. Additionally, many prior flow-through systems require multimode cavities or otherwise operate in multimode fashion. Finally, conventional flow-through systems can often handle homogeneous liquids at high pressure or heterogeneous mixtures at low pressures, but cannot provide a continuous flow reaction system for carrying out high pressure reactions on heterogeneous materials. Because higher pressures (e.g. up to 250 psi or more) are advantageous to or necessary for certain reaction schemes, the ability to carry them out on an automated or flow through basis presents a function disadvantage.
Prior descriptions of proposed (or actual) flow-through or continuous devices tend to reflect—even if by silence—these limitations.
For example, U.S. Pat. No. 5,387,397 to Strauss discloses a flow-through microwave instrument that can normally provide “a continuous and pressurized feed of liquid or slurry to and through a microwave heating zone” (column 2, lines 46–47). Of the approximately 27 actual examples included in the '397 patent, however, only two refer explicitly to the use of a heterogeneous mixture. In particular, the preparation of 4-(1-cyclohex-1-enyl) morpholine at column 11, line 62 uses a finely ground starting material in a solvent, and the preparation of phenyl vinyl ketone at column 12, line 16 describes a suspension of 5 grams of starting material in 400 milliliters of water. Other examples may create heterogeneous mixtures, but if so, Strauss does not appear to focus upon them.
Stated differently, the heterogeneous mixtures described by Strauss are in the neighborhood of about one percent by weight of the otherwise liquid volume being pumped. Furthermore, although Strauss refers to pressure control, it is in the nature of a continuous flow system and does not provide for extended residence times.
Katschnig U.S. Pat. No. 5,403,564 describes a microwave system for thermal decontamination of “pumpable or pourable” material, but essentially operates at between one and two atmospheres.
Knapp U.S. Pat. No. 5,672,316 describes a flow-through system in which higher pressure is equilibrated by placing a flow path within a pressure-containing vessel while leaving one end of the flow path open to the interior of the vessel and a reservoir of liquid in the vessel to thereby cause the pressure on the inside and the outside of the flow path to be identical.
Haswell U.S. Pat. No.5,215,715, which is commonly assigned with the present invention, describes a flow-through system in which samples to be digested are moved through a microwave cavity as discreet slugs at pressures of between about 30 and 120 pounds per square inch (PSI). The Haswell instrument is primarily for digestion rather than chemical synthesis as indicated by the nature of the flow-through system and the manner in which the slug and solvent are pumped through it.
Renoe U.S. Pat. No. 5,420,039, which is also commonly assigned with the present invention, describes a flow-through system in which water is pumped through at high pressure, but an ordinary sample is carried by the water rather than being pressurized. In particular, pressure is controlled in the '039 patent for the purpose of keeping gasses dissolved in a liquid sample so that the liquid sample can be consistently evaluated using a capacitance detection system.
As noted in the parent application, one of the purposes of the flow-through instrument is to provide the capability to use reactants that can include highly-viscous liquids, solids, suspensions, colloids and other liquid-solid mixtures. The viscous, heterogeneous and multi-phase characteristics of such mixtures, however, raise some additional problems.
First, even small variations in the composition of liquid-solid mixtures can create difficulties in handling and pumping such mixtures in small lines (e.g. 0.60 inch in preferred embodiments of the instrument in the parent application) and the associated valves and pumps. As a result, the flow path through the instrument can be susceptible to clogging. If the instrument is being attended by a technician, such clogging can be addressed relatively easily. One of the advantages of contemporary instruments, however, and one of their intended functions, is the capability to run in an automated fashion. Thus, although clogging can be addressed by a technician, preferred equipment should minimize or eliminate the necessity for the technician's presence. Accordingly, the need remains for an enhanced capability for such unattended automation. A need particularly exists for addressing the problem of clogging when solid-liquid mixtures are used in instruments such as that described in the parent application.
As another problem, the effect of microwave radiation on all such solid-liquid mixtures, whether suspensions or otherwise, is best carried out when the mixture is maintained in as consistent a form as possible. In order to carry this out, the usual technique is to stir or otherwise agitate the mixture during the application of microwaves and during the desired reactions.
One convenient method of stirring is the use of a magnetic stirrer, the basic form of which is familiar to most chemists. A magnetic stirrer operates by placing a small magnet, typically covered with a protective polymer such as PTFE (e.g. Teflon®), inside the reaction vessel. An external rotating magnet, typically motor driven with a variable speed switch, is then placed adjacent the reaction vessel so that the motor-driven rotation of the external magnet drives the rotation of the stirrer bar inside the vessel.
This arrangement has been used with some success in microwave instruments, including the instrument described in the parent application and other instruments designed and manufactured by the assignee of the present invention. As those familiar with the operation of magnets are aware, however, the strength of a magnetic field is inversely proportional to the square of the distance from the magnet. Thus, in the case of a magnetic stirrer, as the distance between the stirrer bar in the vessel and the driving magnet increases, the strength of the coupling between the two decreases geometrically.
In particular, it has been found that it is difficult to drive a stirrer bar in a suspension in a reaction vessel in a microwave cavity of certain instruments, including those instruments described in the parent application. In turn, if the stirring cannot be carried out vigorously enough, the effect of the microwaves on the mixture will be inconsistent and reaction yields will suffer accordingly.
Therefore, a need exists for improving techniques for agitating mixtures to an appropriate consistency while they are being exposed to microwave radiation in instruments such as those described in the parent application.